Despite the recent introduction of highly effective antivirals for HCV infection, development of an HCV vaccine remains a high priority in order to curb the epidemic in all parts of the world and in populations with ongoing exposure risk. Given that it is unclear whether sterilizing immunity can be achieved, it is paramount to explore vaccine approaches that deliver protection through prevention of chronic infection. The model for this kind of protection from chronic infection and disease are the roughly 20-30% of people who are able to control HCV spontaneously, usually within 6 months of infection. The large cohorts of patients with acute HCV infection we have assembled through our clinical cores allow us to systematically define what distinguishes such a protective immune response from responses unable to control infection. A better definition of the critical and necessary characteristics of protective immunity will allow to design and test HCV vaccines that deliver the optimal immune response lading to protection from HCV. Overall the scientific hypothesis of project is that HCV-specific CD4 T cell responses are critical for directing the complex host response to HCV and thus that the quality of the induced CD4 response is a key factor for the success of a protective vaccine. Two key elements define effective T helper responses; 1) The persistence of the response in the face of high viral titers and 2) the quality of the T helper response and what kind of immune response it orchestrates by other arms of the immune system. Thus in our first aim we will define the critical cellular networks that are associated with lasting and effective CD4 help. We will also test whether the clonal repertoire of the HCV-specific CD4 T cell response is related to the durability of the response and whether distinct clones of the same CD4 specificity possess different qualities in the T help they provide or are transcriptionally controlled in different ways. In aim 2 we will further define the essential qualities of HCV-specific CD8 T cell responses that mediate HCV control and how these effective CD8 responses are modulated by HCV-specific CD4 help. Together, our investigations will define the qualities of the CD4 and CD8 response that should be elicited by a protective HCV vaccine. Our CD4 analysis will also inform additional investigations throughout the center and its collaborators related to other arms of the immune response depending on effective CD4 help. Beyond HCV, the results will also be of great importance to the field of human immunology in general; while it is universally assumed that CD4 T cells are central to an effective host immune response, the details of how CD4 T cells orchestrate the immune response in humans remain poorly understood.